Obesity leads to an increased risk for type 2 diabetes, heart attack, many types of cancer, hypertension, stroke, and is estimated to soon be the leading cause of death in the US. Through twin and family studies, obesity has been found to have a 40-70% heritability rate, pointing to a strong genetic etiology. The long-term objective of our research is to understand the cellular and molecular basis of long-term regulation of energy homeostasis in order to identify genes in which mutations cause obesity in humans and to discover new targets for the treatment of obesity. This research proposal focuses on the G-protein coupled Melanocortin-4 Receptor (MC4R), a gene expressed in the central nervous system and implicated in the regulation of food intake. Different mutations in the coding sequence of MC4R cause severe obesity in humans. In this proposal we will extend these previous findings by determining whether rare mutations in non-coding regulatory sequences of MC4R could be a cause of severe obesity. In addition, we have recently found that MC4R is expressed at the primary cilium, a cellular organelle that serves as a signaling hub for eukaryotic cells in general and neurons in particular. Another aim of our studies will be to determine the functional determinants of MC4R localization at the primary cilium as well as the effect of human-obesity associated mutations on this localization.